Preparation method of 2-amino-3-methyl-5-chlorobenzoic acid compound
The synthetic route of 2-amino-3-methyl-5-chlorobenzoic acid compounds was optimized by combining halogenated compounds with 4-dimethylaminopyridine and bases and hydrogenating with metal catalysts. This solved the problems of numerous byproducts and high costs in the existing technology, and achieved efficient and low-cost production.
Patent Information
- Application Number
- CN202511700157.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-11-19
- Publication Date
- 2026-02-24
AI Technical Summary
Existing methods for synthesizing 2-amino-3-methyl-5-chlorobenzoic acid compounds suffer from problems such as numerous byproducts and high process costs, especially due to the use of expensive nanomaterial catalysts and complex purification processes.
Compound II was prepared by reacting a compound of formula III with a halogenated compound and a base in the presence of 4-dimethylaminopyridine. Compound I was then prepared by hydrogenation catalyzed by a metal catalyst such as Ni-Mo/Al2O3 or Co-Mo/TiO2. The reaction conditions were optimized to improve the yield.
The synthesis of 2-amino-3-methyl-5-chlorobenzoic acid compounds with fewer byproducts and lower process costs has been achieved, improving reaction yield and reducing production costs.
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Figure CN121554404A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of intermediate compound preparation, specifically to the preparation of an important intermediate compound, 2-amino-3-methyl-5-chlorobenzoic acid. Background Technology
[0002] 2-Amino-3-methyl-5-chlorobenzoic acid compounds serve as important intermediates in the synthesis of compounds such as chlorantraniliprole. However, research on their synthetic methods is currently limited. Patent CN117720426A discloses a method for synthesizing 2-amino-3-methyl-5-chlorobenzoic acid, as shown in the following synthetic route. This route uses 2-amino-5-chlorobenzoic acid in the presence of m-methylbenzoic acid, catalyzed by supported iron-based nanomaterials, to generate 2-amino-3-methyl-5-chlorobenzoic acid from the methyl group at the 3-position of 2-amino-5-chlorobenzoic acid. While the reaction is simple, it requires purification of the raw materials 2-amino-5-chlorobenzoic acid and m-methylbenzoic acid before the reaction. Furthermore, the use of relatively expensive nanomaterials as catalysts reduces its industrial applicability.
[0003] Summary of the Invention
[0004] In view of the various defects in the preparation of 2-amino-3-methyl-5-chlorobenzoic acid compounds disclosed in the prior art, the present invention provides a method for synthesizing 2-amino-3-methyl-5-chlorobenzoic acid compounds with fewer by-products and lower process cost.
[0005] Specifically, this invention first provides a method for synthesizing compound II, wherein compound III is reacted with compound A in a solvent in the presence of a halide, 4-dimethylaminopyridine, and a base to prepare compound II. The synthetic route is as follows:
[0006]
[0007] in,
[0008] R1 is selected from H or optionally substituted C1-C6 alkyl; R2 is selected from optionally substituted C1-C6 alkyl or optionally substituted C1-C6 alkyl thio group;
[0009] The halogenated compound is one or more of cyanuric chloride, NCS, dichlorohydantoin, dibromohydantoin, or NBS.
[0010] This invention also provides a method for preparing a compound of formula I, wherein a compound of formula II is prepared by hydrogenation reaction in the presence of a metal catalyst, and the synthetic route is as follows:
[0011]
[0012] R1 and R2 are defined as described above.
[0013] Beneficial effects of this invention:
[0014] 1. The preparation of the compound of formula II of the present invention was achieved by screening the combination of 4-dimethylaminopyridine and base, which yielded higher yields than those without 4-dimethylaminopyridine.
[0015] 2. In the preparation process of Formula I of this invention, the reaction yield was improved by screening suitable metal catalysts. Detailed Implementation
[0016] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "comprising of," etc., will be understood to include the stated components or steps, without excluding other substances or steps.
[0017] Furthermore, to better illustrate the present invention, numerous specific details are provided in the following detailed embodiments.
[0018] Those skilled in the art will understand that the present invention can be practiced even without certain specific details. In some embodiments, materials, methods, and means well known to those skilled in the art are not described in detail in order to highlight the spirit of the invention.
[0019] In this invention, percentage content refers to mass percentage unless otherwise specified.
[0020] In the above statements, the term "alkyl" used alone or in compound words such as "alkylthio" includes straight-chain alkyl or branched alkyl, such as methyl, ethyl, n-propyl, isopropyl or different butyl isomers.
[0021] Optional substitution means that it can be substituted or not. When it is substituted, the substituents are preferably halogens, nitros, cyano groups, etc., but are not limited to these.
[0022] Halogens refer to fluorine, chlorine, bromine, and iodine.
[0023] This invention first provides a method for preparing compound II, wherein compound III is reacted with compound A in a solvent in the presence of a halide, 4-dimethylaminopyridine, and a base to prepare compound II. The synthetic route is as follows:
[0024]
[0025] in,
[0026] R1 is selected from H or optionally substituted C1-C6 alkyl; R2 is selected from optionally substituted C1-C6 alkyl or optionally substituted C1-C6 alkyl thio group;
[0027] The halogenated compound is one or more of cyanuric chloride, NCS, dichlorohydantoin, dibromohydantoin, or NBS.
[0028] Preferably, R1 is H or C1-C6 alkyl, more preferably H, methyl, ethyl, propyl, butyl, pentyl or hexyl; R2 is C1-C6 alkyl or C1-C6 alkylthio, preferably methyl, ethyl, propyl, methylthio, ethylthio or propylthio.
[0029] Preferably, under conditions of -20 to 100°C, Formula III and Compound A are added to the solvent.
[0030] Then, the halogenated product is added in batches, and the mixture is stirred for 0.5-1 hour after the addition is complete. Then, 4-dimethylaminopyridine (DMAP) and alkali are added.
[0031] Preferably, in the above method, after adding 4-dimethylaminopyridine (DMAP) and alkali, the reaction is carried out at 40-100°C for 1-5 hours.
[0032] Preferably, the alkali described above is an organic alkali or an inorganic alkali; preferably, it is one or more of sodium methoxide, sodium ethoxide, sodium propoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium propoxide, potassium tert-butoxide, butyllithium, methylamine, dimethylamine, triethylamine, diisopropylethylamine, pyridine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate.
[0033] Preferably, the amount of 4-dimethylaminopyridine (DMAP) is 0.001 equivalents (molar equivalents) or more of the compound of formula III, which can provide a good reaction yield. More preferably, when the amount of 4-dimethylaminopyridine (DMAP) reaches 0.005 equivalents (molar equivalents) of the compound of formula III, the reaction yield is significantly improved.
[0034] Preferably, the solvent mentioned above is one or more of dichloromethane, dichloroethane, chloroform, n-hexane, tetrahydrofuran, dioxane, acetonitrile, diethyl ether, petroleum ether, ethyl acetate, methanol, ethanol, acetone, or DMF.
[0035] This invention also provides a method for preparing compound I, wherein compound II is reacted with hydrogen gas in the presence of a metal catalyst to obtain compound I. The synthetic route is as follows:
[0036]
[0037] in,
[0038] R1 is selected from H or optionally substituted C1-C6 alkyl; R2 is selected from optionally substituted C1-C6 alkyl or optionally substituted C1-C6 alkyl thio group;
[0039] Preferably, R1 is H or a C1-C6 alkyl group, more preferably H, methyl, ethyl, propyl, butyl, pentyl, or hexyl; R2 is a C1-C6 alkyl or C1-C6 alkylthio group, preferably methyl, ethyl, propyl, methylthio, ethylthio, or propylthio; particularly preferably methylthio. Studies have shown that when R2 is methylthio, the hydrogenation reaction is more readily carried out.
[0040] Preferably, the reaction time for introducing hydrogen gas is 1-5 hours, and the reaction pressure is 0.1-1 MPa.
[0041] Preferably, in the preparation method of the compound of Formula I above, the metal catalyst is one or more of Ni-Mo / Al2O3, Co-Mo / Al2O3, Ni-Mo / TiO2, or Co-Mo / TiO2, with Ni-Mo / Al2O3 or Ni-Mo / TiO2 being more preferred. The preferred metal catalyst exhibits superior technical performance.
[0042] Preferably, in the preparation method of the compound of Formula I above, the reaction is carried out in a solvent, wherein the solvent is selected from one or more of dichloromethane, dichloroethane, chloroform, n-hexane, tetrahydrofuran, dioxane, diethyl ether, petroleum ether, ethyl acetate, methanol, ethanol or DMF.
[0043] The present invention will be further described below with reference to embodiments. Those skilled in the art can utilize the present invention to the fullest extent using the above description. Therefore, the following examples should be understood as illustrative only and do not limit the disclosure of the present invention in any way. The methods in the following examples illustrate the process of each step in the entire synthetic transformation, and the raw materials used in each step must or may not be obtained by the specific preparation steps described in other examples or steps.
[0044] Example
[0045] Example 1: Synthesis of 2-amino-3-methyl-5-chlorobenzoic acid
[0046] Take 150 ml of tetrahydrofuran, add 8.58 g of 2-amino-5-chlorobenzoic acid and 3.72 g of dimethyl sulfide at 50 °C, add 7.34 g of NCS in portions, stir at room temperature for 0.5 h, then add 0.061 g of DMAP and 3.51 g of sodium methoxide, react at 60 °C for 3 h, after the reaction is completed, cool to room temperature, add alkaline water, extract with dichloroethane, take the organic layer and concentrate to obtain 2-amino-3-methylthiomethyl-5-chlorobenzoic acid (11.28 g, yield 97.4%).
[0047] Take 150 ml of dichloromethane, add 11.28 g of 2-amino-3-methylthiomethyl-5-chlorobenzoic acid and 3.76 g of Ni-Mo / Al2O3 (15% loading), and react with hydrogen gas at room temperature for 1.5 h. After the reaction is complete, filter and concentrate the filtrate to obtain 2-amino-3-methyl-5-chlorobenzoic acid (8.72 g, yield 96.5%).
[0048] Example 2: Synthesis of methyl 2-amino-3-methyl-5-chlorobenzoate
[0049] Take 150 ml of dichloroethane, add 9.28 g of methyl 2-amino-5-chlorobenzoate and 3.72 g of dimethyl sulfide at 60 °C, add 8.01 g of NCS in portions, stir at room temperature for 0.5 h, then add 0.061 g of DMAP and 5.57 g of triethylamine, react at 70 °C for 2 h, after the reaction is complete, cool to room temperature and add alkaline water, take the organic layer and concentrate to obtain methyl 2-amino-3-methylthiomethyl-5-chlorobenzoate (12.06 g, yield 98.2%).
[0050] 1H NMR (300MHz, CDCl3): δ7.85(s,1H), δ7.26(s,1H), δ5.67(s,2H), δ3.89(s,3H), 3.72(s,2H), δ2.00(s,3H)
[0051] Take 150 ml of ethanol, add 12.06 g of methyl 2-amino-3-methylthiomethyl-5-chlorobenzoate and 2.52 g of Ni-Mo / TiO2 (15% loading), and react with hydrogen gas at room temperature for 1 h. After the reaction is complete, filter and concentrate the filtrate to obtain methyl 2-amino-3-methyl-5-chlorobenzoate (9.64 g, yield 98.4%).
[0052] 1H NMR (300MHz, deuterated DMSO): δ7.54(s,1H), δ7.24(s,1H), δ6.60(s,2H), δ3.75(s,3H), δ2.09(s,3H)
[0053] Example 3: Synthesis of methyl 2-amino-3-methylthiomethyl-5-chlorobenzoate
[0054] Take 150 ml of dichloroethane, add 9.28 g of methyl 2-amino-5-chlorobenzoate and 3.72 g of dimethyl sulfide at 60 °C, add 8.01 g of NCS in portions, stir at room temperature for 0.5 h, then add 5.57 g of triethylamine, react at 70 °C for 2 h, after the reaction is complete, cool to room temperature and add alkaline water, take the organic layer and concentrate, and prepare liquid phase purification to obtain methyl 2-amino-3-methylthiomethyl-5-chlorobenzoate (5.75 g, yield 46.8%).
[0055] Example 4: Synthesis of methyl 2-amino-3-methylthiomethyl-5-chlorobenzoate
[0056] Take 150 ml of dichloroethane, add 9.28 g of methyl 2-amino-5-chlorobenzoate and 3.72 g of dimethyl sulfide at 60 °C, add 8.01 g of NCS in portions, stir at room temperature for 0.5 h, then add 0.006 g of DMAP and 5.57 g of triethylamine, react at 70 °C for 2 h, after the reaction is completed, cool to room temperature and add alkaline water, take the organic layer and concentrate, and prepare liquid phase purification to obtain methyl 2-amino-3-methylthiomethyl-5-chlorobenzoate (7.47 g, yield 60.8%).
[0057] Example 5: Synthesis of ethyl 2-amino-3-methyl-5-chlorobenzoate
[0058] Take 150 ml of dioxane, add 9.98 g of ethyl 2-amino-5-chlorobenzoate and 5.18 g of dimethyl disulfide at 85 °C, then add 11.82 g of dichlorohydantoin in portions. Stir at room temperature for 0.5 h, then add 0.031 g of DMAP and 3 g of sodium hydroxide. React at 90 °C for 1 h. After the reaction is complete, cool to room temperature, add alkaline water, extract with dichloroethane, and concentrate the organic layer to obtain ethyl 2-amino-3-methyldithiomethyl-5-chlorobenzoate (14.36 g, yield 98.4%).
[0059] Take 150 ml of methanol, add 14.36 g of ethyl 2-amino-3-methyldithiomethyl-5-chlorobenzoate and 9.3 g of Ni-Mo / TiO2 (15% loading), and react with hydrogen gas at room temperature for 0.5 h. After the reaction is complete, filter and concentrate the filtrate to obtain ethyl 2-amino-3-methyl-5-chlorobenzoate (10.4 g, yield 99%).
[0060] Example 6: Synthesis of ethyl 2-amino-3-methyldithiomethyl-5-chlorobenzoate
[0061] Take 150 ml of dioxane, add 9.98 g of ethyl 2-amino-5-chlorobenzoate and 5.18 g of dimethyl disulfide at 85 °C, then add 11.82 g of dichlorohydantoin in portions. Stir at room temperature for 0.5 h, then add 0.027 g of DMAP and 3 g of sodium hydroxide. React at 90 °C for 1 h. After the reaction is complete, cool to room temperature, add alkaline water, extract with dichloroethane, concentrate the organic layer, and purify to obtain ethyl 2-amino-3-methyldithiomethyl-5-chlorobenzoate (11.2 g, yield 76.8%).
[0062] Example 7: Synthesis of ethyl 2-amino-3-methyl-5-chlorobenzoate
[0063] Take 150 ml of dichloroethane, add 9.98 g of ethyl 2-amino-5-chlorobenzoate and 3.72 g of dimethyl sulfide at 60 °C, add 8.01 g of NCS in portions, stir at room temperature for 0.5 h, then add 6.72 g of DMAP, react at 70 °C for 2 h, after the reaction is complete, cool to room temperature and add alkaline water, take the organic layer and concentrate to obtain ethyl 2-amino-3-methylthiomethyl-5-chlorobenzoate (10.86 g, yield 83.6%).
[0064] Take 150 ml of methanol, add 10.86 g of ethyl 2-amino-3-methylthiomethyl-5-chlorobenzoate and 9.3 g of Ni-Mo / TiO2 (15% loading), and react with hydrogen gas at room temperature for 0.5 h. After the reaction is complete, filter, concentrate the filtrate, and prepare liquid phase purification to obtain ethyl 2-amino-3-methyl-5-chlorobenzoate (6.49 g, yield 72.7%).
[0065] Example 8: Synthesis of Isopropyl 2-amino-3-methyl-5-chlorobenzoate
[0066] Take 350 ml of chloroform, add 16.02 g NCS, 21.36 g isopropyl 2-amino-5-chlorobenzoate, and 7.44 g dimethyl sulfide at -10 °C, stir at room temperature for 0.5 h, then add 0.084 g DMAP and 23.74 g pyridine, react at 60 °C for 3 h, after the reaction is completed, cool to room temperature and add alkaline water, take the organic layer and concentrate to obtain isopropyl 2-amino-3-methylthiomethyl-5-chlorobenzoate (26.82 g, yield 98%).
[0067] Take 150 ml of ethanol, add 13.41 g of 2-amino-3-methylthiomethyl-5-chlorobenzoate isopropyl ester and 8.9 g of Ni-Mo / TiO2 (15% loading), and react with hydrogen gas at room temperature for 1 h. After the reaction is complete, filter and concentrate the filtrate to obtain 2-amino-3-methyl-5-chlorobenzoate isopropyl ester (11.0 g, yield 98.6%).
[0068] Example 9: Synthesis of Isopropyl 2-amino-3-methyl-5-chlorobenzoate
[0069] Take 150 ml of ethanol, add 13.41 g of 2-amino-3-methylthiomethyl-5-chlorobenzoate isopropyl ester and 1.34 g of Raney nickel, and react with hydrogen gas at room temperature for 1 h. After the reaction is complete, filter and concentrate the filtrate to obtain 2-amino-3-methyl-5-chlorobenzoate isopropyl ester (6.8 g, yield 60.9%).
[0070] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Any simple modifications, alterations, and equivalent changes made to the above embodiments based on the technical essence of the present invention shall still fall within the protection scope of the present invention.
Claims
1. A method for preparing a compound of formula II, characterized in that, Compound III was reacted with compound A in a solvent in the presence of a halide, 4-dimethylaminopyridine, and a base to prepare compound II. The synthetic route is as follows: in, R1 is selected from H or optionally substituted C1-C6 alkyl; R2 is selected from optionally substituted C1-C6 alkyl or optionally substituted C1-C6 alkyl thio group; The halogenated product is one or more of cyanuric chloride, NCS, dichlorohydantoin, dibromohydantoin, or NBS; The amount of 4-dimethylaminopyridine added is not less than 0.001 molar equivalents of the compound of formula III.
2. The preparation method according to claim 1, characterized in that, R1 is H or C1-C6 alkyl, preferably H, methyl, ethyl, propyl, butyl, pentyl or hexyl; R2 is C1-C6 alkyl or C1-C6 alkylthio, preferably methyl, ethyl, propyl, methylthio, ethylthio or propylthio.
3. The preparation method according to claim 1 or 2, characterized in that, The alkali mentioned is an organic alkali or an inorganic alkali.
4. The preparation method according to claim 3, characterized in that, The alkali is one or more of sodium methoxide, sodium ethoxide, sodium propoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium propoxide, potassium tert-butoxide, butyllithium, methylamine, dimethylamine, triethylamine, diisopropylethylamine, pyridine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate.
5. The preparation method according to claim 1, characterized in that, The solvent is one or more of dichloromethane, dichloroethane, chloroform, n-hexane, tetrahydrofuran, dioxane, acetonitrile, diethyl ether, petroleum ether, ethyl acetate, methanol, ethanol, acetone, or DMF.
6. A method for preparing a compound of formula I, characterized in that, Compound II was prepared by hydrogenation in the presence of a metal catalyst to yield compound I. The synthetic route is as follows: Wherein, R1 and R2 are defined as in claims 1-5; the compound of formula II is prepared by the preparation method according to any one of claims 1-5.
7. The preparation method according to claim 6, characterized in that, The metal catalyst is one or more of Ni-Mo / Al2O3, Co-Mo / Al2O3, Ni-Mo / TiO2 or Co-Mo / TiO2, preferably Ni-Mo / Al2O3 or Ni-Mo / TiO2.
8. The preparation method according to claim 6, characterized in that, The reaction is carried out in a solvent selected from one or more of dichloromethane, dichloroethane, chloroform, n-hexane, tetrahydrofuran, dioxane, diethyl ether, petroleum ether, ethyl acetate, methanol, ethanol, or DMF.